1. Mitochondrial Ca2+-dependent NLRP3 activation exacerbates the Pseudomonas aeruginosa-driven inflammatory response in cystic fibrosis.
- Author
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Rimessi A, Bezzerri V, Patergnani S, Marchi S, Cabrini G, and Pinton P
- Subjects
- Bronchi metabolism, Bronchi microbiology, Bronchi pathology, Calcium Channels genetics, Calcium Channels metabolism, Calcium Signaling, Carrier Proteins agonists, Carrier Proteins metabolism, Cells, Cultured, Cystic Fibrosis genetics, Cystic Fibrosis microbiology, Cystic Fibrosis pathology, Cystic Fibrosis Transmembrane Conductance Regulator, Epithelial Cells microbiology, Epithelial Cells pathology, Flagellin genetics, Flagellin metabolism, Gene Expression Regulation, Host-Pathogen Interactions, Humans, Inflammation, Interleukin-18 biosynthesis, Interleukin-18 metabolism, Interleukin-1beta biosynthesis, Interleukin-1beta metabolism, Mitochondria microbiology, Mitochondria pathology, NLR Family, Pyrin Domain-Containing 3 Protein, Pseudomonas aeruginosa pathogenicity, Calcium metabolism, Carrier Proteins genetics, Cystic Fibrosis metabolism, Epithelial Cells metabolism, Mitochondria metabolism, Pseudomonas aeruginosa physiology
- Abstract
The common pathological manifestation of cystic fibrosis (CF) is associated with an excessive lung inflammatory response characterized by interleukin-1β accumulation. CF airway epithelial cells show an exacerbated pro-inflammatory response to Pseudomonas aeruginosa; however, it is unclear whether this heightened inflammatory response is intrinsic to cells lacking CF transmembrane conductance regulator (CFTR). Here we demonstrate that the degree and quality of the inflammatory response in CF are supported by P. aeruginosa-dependent mitochondrial perturbation, in which flagellin is the inducer and mitochondrial Ca(2+) uniporter (MCU) is a signal-integrating organelle member for NLRP3 activation and IL-1β and IL-18 processing. Our work elucidates the regulation of the NLRP3 inflammasome by mitochondrial Ca(2+) in the P. aeruginosa-dependent inflammatory response and deepens our understanding of the significance of mitochondria in the Ca(2+)-dependent control of inflammation.
- Published
- 2015
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